A recent paper published in Nature Medicine has sparked a major controversy. Emotions seem to be running high since one of the mainstream nutritional products, l-carnitine, has been implicated in causing atherosclerosis or formation of plaque in the blood vessels and thus increasing the likelihood of strokes, heart attacks and even death!
L-Carnitine is the mainstay and a key supplement ingredient used in many of the nutritional programs for achieving optimal health. It is widely sold in health food stores, pharmacies, by many naturopathic clinics, and is popular among sport athletes, for weight loss, heart health, for increasing the endurance, as well as for a host of other conditions.
The recent study has found an interesting and a provocative link between the consumption of red meat, l-carnitine, and the trillions of diverse bacteria that are housed in our gut and collectively referred to as the microbiota. Researchers have long known that red meat consumption was associated with increased heart disease. Originally it was thought that it was the saturated fat and cholesterol content of the red meat that was the culprit. However, further studies have shown that contents of these harmful substances weren’t enough to be the cause and something else was at work.
Last year, researchers from the US found that l-carnitine, an amino acid particularly rich in red meat, was converted by the microbiota into a more harmful substance called trimethylamine oxide (TMAO). It is this substance rather than l-carnitine itself that is likely to be the causative factor according to the researchers for clogging up the arteries with cholesterol deposits. The fact that TMAO is formed by the microbes resident in the digestive tract is disturbing since many researchers have long argued that there is an interaction between the nutrients we get from our diet and the bacteria themselves. This interaction can be positive as well as negative. Essentially, the microbes perform protective biological functions in the body including: reducing toxins like cancer causing substances called carcinogens to less harmful substances, or making important vitamins like vitamin K upon which our bodies depend. However, they may also produce substances that are even more toxic like TMAO that can do the body harm.
Using elegant experiments, the researchers used both animals and humans to test their hypothesis that the carnitine in red meat is converted into TMAO and will cause hardening of the blood vessels.
The first set of experiments used mice that were fed regular chow or l-carnitine enriched chow. As expected, they found mice fed carnitine-enriched chow had higher levels of TMAO and their blood vessels eventually became laden with cholesterol plaque, while regular chow-fed mice were free of such vessel abnormalities because no TMAO was formed. Next, the researchers gave the carnitine-fed mice antibiotics to kill the gut bacteria so no TMAO could be formed. Indeed, these mice even when fed the carnitine rich chow had relatively healthy arteries indicating that it is the bacteria that convert carnitine into the more dangerous TMAO.
Researchers then looked at humans and compared twenty-six vegetarians and fifty- one omnivores. They found that in the vegetarians, the TMAO levels were relatively normal unlike the omnivores who had much higher levels of TMAO. Even when five vegetarians were challenged with supplemental carnitine, their TMAO levels remained lower than the TMAO levels of five omnivores fed the same amount of carnitine. According to the researchers, these finding suggest that the microbiota of the vegetarians is different to the omnivores. The omnivores are more prone to heart disease due to increased TMAO formation. While the vegetarians have a different microbiota, even when consuming supplemental carnitine, they do not readily form TMAO. This is an interesting finding in that the vegetarians have developed not only a different mix of microbes, since they are not used to eating meat, the principal source of carnitine, but also have lost the capabilities of forming TMAO. The omnivores having regular access to carnitine via red meat consumption have a particularly rich mix of microbiota that are adapted to dealing with carnitine and thus forming excessive amounts of TMAO.
All this seems rather alarming, and various questions arise including, is this study rigorous and does it have any merit? And more importantly, what does this mean for the carnitine supplement consumer?
First, the animal data from the study does seem robust and quite convincing; however, the usual concern is its translatability to humans. Mice (at least lab mice) are typically not a carnivore and thus the dietary effects of carnitine may be quite different to humans who are generally omnivores.
Second, the researchers did look at a large group of patients (2,595) with various heart related abnormalities and noted a strong dose-dependent correlation between blood carnitine levels and various heart diseases. In other words, the higher the carnitine levels in the blood and thus higher TMAO levels, the greater the risk of heart disease. There are however, the usual concerns about various confounding (complicating) factors such as the influences of smoking and body weight on the study results (there were overweight and lean patients in the study group). While the researchers do mention they adjusted for various confounding factors, this cannot be ignored as causing a bias. The researchers also failed to add a reference group which would have helped the comparison between healthy and diseased patients. Of course many of the human data are associative and there may be many confounding factors in life style between obese and lean patients, but also between vegetarians and omnivores (vegetarians may have been a more healthy group, perhaps eating more fiber and/or exercising more than omnivores), additionally extra fiber in the diet may support the intestinal bacteria in the vegetarians and these differences cannot be ignored.
We must also note that many carnitine studies have been published, and while the results have been conflicting and showing either positive results or no benefit at all, there have been no studies to date that have mentioned any severe negative health effects like heart disease. The recent meta-analysis of thirteen l-carnitine studies did not find any evidence of l-carnitine causing heart related or for that matter other side-effects. However, one could argue that most of these studies were of short duration, a few months at the most, and not of sufficient time for cholesterol deposits to manifest in the blood vessels.
Overall, the researchers make the following conclusions: First, red meat is not so good for heart health, but most people know that anyway. Second, meat eaters who supplement with carnitine should exercise caution when doing so as this may further increase the risk of heart disease. Third, vegetarians (who probably need supplemental carnitine since they do not get it from their diet) while initially not having an increased risk of heart disease, may over time be prone to an increased risk since their microbiota may re-adapt to act in the same way as those of carnivores.
However, there is one serious flaw in the study and that is, there are many foods and nutrients with high levels of TMA (a precursor to TMAO) that are regularly consumed including: grains and cereals and leafy green vegetables like beets and spinach; these are loaded with TMA containing compounds including betaine and choline with levels likely to be greater than in a steak. The previous 2011 study by the same group reported that nutrients like choline and betaine when fed to mice were also responsible for increased TMAO levels and thus caused heart disease. Yet, this is contrary to the current evidence and in fact these nutrients are themselves part of many nutritional supplements used every day including those intended to counteract heart disease! Moreover, many vegetarians regularly consume foods like beets and spinach as well as TMA rich nutrients like choline and betaine. Another common source of TMA is soy, especially as a metabolite of lecithin. If anyone ever complains of a “fishy” odor after consuming lecithin, it’s a result of excess TMA formation. How is it that this group isn’t populated with TMA transforming bacteria which can convert these compounds to the toxic TMAO and cause heart disease?
In conclusion, there are weaknesses in the hypothesis that l-carnitine causes heart disease via a toxic metabolite TMAO, plus carnitine has not been associated with negative heart health risk in previous studies. As always more studies are required. Image by © 2007 Monkey Business via DollarPhotoClub
Wang Z et-al, “Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease” Nature 2011; 472: 57-63
Di Nicolantonio JJ “L-Carnitine in the secondary prevention of cardiovascular disease: Systematic review and meta-analysis” Mayo Clin Proc. 2013 April online
Koeth R et-al “Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis” Nature Medicine published online April 7, 2013